Oral pharmaceutical compositions of nicotinamide

Abstract

Described herein are pharmaceutical compositions for the oral administration of nicotinamide, or a combination of nicotinamide and mesalazine, as well as methods of making such pharmaceutical compositions, and therapeutic methods for using them. The compositions comprise delayed-immediate release and delayed-extended release formulation of nicotinamide or a combination of nicotinamide and mesalazine.

What is claimed is: 
     
       1. A unit dose pharmaceutical product formulated for oral administration of nicotinamide to a subject, comprising:
 (a) a plurality of delayed-immediate release minitablets comprising a compressed matrix comprising nicotinamide provided with a pH-dependent enteric coating, wherein the delayed-immediate release minitablets selectively release nicotinamide at a pH of about 5.5 or greater in the distal ileum; and 
 (b) a plurality of delayed-extended release minitablets comprising a compressed matrix comprising nicotinamide provided with an inner pH-independent extended release coating and an outer pH-dependent enteric coating, wherein the delayed-extended release minitablets selectively release nicotinamide at a pH of about 7 or greater in the colon; 
 optionally, wherein (a) and (b) are provided in a sachet, capsule, or vial; 
 wherein: 
 the relative amounts of (a) and (b) in the unit dose pharmaceutical product are such that from 10 to 90% w/w of the nicotinamide provided in the unit dose pharmaceutical is present in the delayed-extended release minitablets of (b); and 
 the total amount of nicotinamide in the unit dose pharmaceutical product is from 0.25 to 6 g. 
 
     
     
       2. The unit dose pharmaceutical product of  claim 1 , wherein, when subject to in vitro dissolution testing according to USP Type 1 Basket at 37° C. and 100 rpm in 500 mL dissolution medium of pH 1.2 buffer for 2 hours, followed by pH 4.5 buffer for 2 hours, followed by pH 7 buffer, the delayed-immediate release minitablets exhibit release of less than 10% of their total nicotinamide content at pH 1.2 and pH 4.5, and exhibit release of all of their total nicotinamide content within 60 minutes at pH 7. 
     
     
       3. The unit dose pharmaceutical product of any one of  claim 1 , wherein, when subject to in vitro dissolution testing according to USP Type 1 Basket at 37° C. and 100 rpm in 500 mL dissolution medium of pH 1.2 buffer for 2 hours, followed by pH 4.5 buffer for 2 hours, followed by pH 7 buffer, the delayed-immediate release minitablets exhibit release of less than 10% of their total nicotinamide content at pH 1.2 and pH 4.5, and exhibit release of all of their total nicotinamide content within 30 minutes at pH 7. 
     
     
       4. The unit dose pharmaceutical product of  claim 1 , wherein the delayed-immediate release minitablets of (a) release at least 50% w/w of their total nicotinamide content in the distal ileum. 
     
     
       5. The unit dose pharmaceutical product of  claim 1 , wherein the delayed-immediate release minitablets of (a) release at least 70% w/w of their total nicotinamide content in the distal ileum. 
     
     
       6. The unit dose pharmaceutical product of  claim 1 , wherein, when subject to in vitro dissolution testing according to USP Type 1 Basket at 37° C. and 100 rpm in 500 mL dissolution medium of pH 1.2 buffer for 2 hours, followed by pH 4.5 buffer for 2 hours, followed by pH 7.0 buffer for 12 hours, the delayed-extended release minitablets exhibit no release of nicotinamide at pH 1.2 and pH 4.5, and exhibit extended release of nicotinamide over at least 4 hours at pH 7.0. 
     
     
       7. The unit dose pharmaceutical product of  claim 1 , wherein, when subject to in vitro dissolution testing according to USP Type 1 Basket at 37° C. and 100 rpm in 500 mL dissolution medium of pH 1.2 buffer for 2 hours, followed by pH 4.5 buffer for 2 hours, followed by pH 7.0 buffer for 12 hours, the delayed-extended release minitablets exhibit no release of nicotinamide at pH 1.2 and pH 4.5, and exhibit extended release of nicotinamide over at least 8-12 hours at pH 7.0. 
     
     
       8. The unit dose pharmaceutical product of  claim 1 , wherein the delayed-extended release minitablets of (b) release at least 50% w/w of their total nicotinamide content in the colon. 
     
     
       9. The unit dose pharmaceutical product of  claim 1 , wherein the delayed-extended release minitablets of (b) release at least 70% w/w of their total nicotinamide content in the colon. 
     
     
       10. The unit dose pharmaceutical product of  claim 1 , wherein the compressed matrix of (a) and the compressed matrix of (b) comprise at least 60% w/w nicotinamide and, optionally, one or more selected from a pharmaceutically acceptable binder, a pharmaceutically acceptable filler, and a pharmaceutically acceptable lubricant. 
     
     
       11. The unit dose pharmaceutical product of  claim 1 , wherein:
 the compressed matrix of (a) and the compressed matrix of (b) each comprise nicotinamide, hydroxylpropyl cellulose, microcrystalline cellulose, and magnesium stearate; 
 the pH-dependent enteric coating of (a) comprises one or more polymers selected from methacrylic acid and ethyl acrylate copolymer 1:1, hypromellose acetate succinate, and hypromellose phthalate; 
 the pH-dependent enteric coating of (b) comprises one or more polymers selected from the group consisting of methacrylic acid and methyl methacrylate copolymer 1:2, poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) [7:3:1] and hypromellose acetate succinate; 
 the pH-independent extended release coating of (b) comprises ethyl cellulose and hydroxypropyl methylcellulose; and 
 optionally, the minitablets of (a) and/or the minitablets of (b) further comprise a seal coat exterior to the pH dependent enteric coating. 
 
     
     
       12. The unit dose pharmaceutical product of  claim 1 , wherein the minitablets of (a) and the minitablets of (b) have a longest diameter of 1-4 mm. 
     
     
       13. A method of administering nicotinamide to a subject in need thereof, or for treating inflammatory bowel disease, comprising orally administering to the subject a unit dose pharmaceutical product according to  claim 1 . 
     
     
       14. A unit dose pharmaceutical product formulated for oral administration of nicotinamide and mesalazine to a subject, comprising:
 (a) a plurality of delayed-immediate release minitablets comprising a compressed matrix comprising nicotinamide provided with a pH-dependent enteric coating, wherein the delayed-immediate release minitablets selectively release nicotinamide at a pH of about 5.5 or greater in the distal ileum; 
 (b) a plurality of delayed-extended release minitablets comprising a compressed matrix comprising nicotinamide provided with an inner pH-independent extended release coating and an outer pH-dependent enteric coating, wherein the delayed-extended release minitablets selectively release nicotinamide at a pH of about 7 or greater in the colon; 
 (c) a plurality of delayed-immediate release minitablets comprising a compressed matrix comprising mesalazine provided with a pH-dependent enteric coating, wherein the delayed-immediate release minitablets selectively release mesalazine at a pH of about 5.5 or greater in the distal ileum; and 
 (d) a plurality of delayed-extended release minitablets comprising a compressed matrix comprising mesalazine provided with an inner pH-independent extended release coating and an outer pH-dependent enteric coating, wherein the delayed-extended release minitablets selectively release mesalazine at a pH of about 7 or greater in the colon; 
 wherein: 
 the relative amounts of (a) and (b) in the unit dose pharmaceutical product are such that from 10 to 90% w/w of the nicotinamide provided in the unit dose pharmaceutical is present in the delayed-extended release minitablets of (b); 
 the relative amounts of (c) and (d) in the unit dose pharmaceutical product are such that from 10 to 90% w/w of the mesalazine provided in the unit dose pharmaceutical is present in the delayed-extended release minitablets of (d); 
 wherein the relative amounts of (a) and (b) may be selected independently of the relative amounts of (c) and (d) and the relative amounts of (c) and (d) may be selected independently of the relative amounts of (a) and (b); 
 the total amount of nicotinamide in the unit dose pharmaceutical product is from 0.25 to 4 g, and the total amount of mesalazine in the unit dose pharmaceutical product is from 0.4 to 6 g. 
 
     
     
       15. A method for orally administering nicotinamide and mesalazine to a subject in need thereof, or for treating inflammatory bowel disease, comprising orally administering a unit dose pharmaceutical product comprising nicotinamide and mesalazine minitablets according to  claim 14 . 
     
     
       16. A method of making a unit dose pharmaceutical product according to  claim 1 , comprising:
 (a) preparing a plurality of delayed-immediate release minitablets (a); 
 (b) preparing a plurality of delayed-extended release minitablets (b); 
 (c) providing (a) and (b) in a sachet, capsule, or vial, thereby obtaining the unit dose pharmaceutical product, wherein: 
 the relative amounts of (a) and (b) in the unit dose pharmaceutical product are such that from 10 to 90% w/w of the nicotinamide provided in the unit dose pharmaceutical is present in the delayed-extended release minitablets of (b), and the total amount of nicotinamide in the unit dose pharmaceutical product is from 0.25 to 6 g.